Synthetic modifications of the vasopressin or oxytocin structures are known to influence profoundly the antagonistic or agonistic activity of the resulting compounds. Predictability is poor in this area of research; F. L. Stassen et al., J. Pharmacology and Experimental Therapeutics, 223 53 (1982).
A. B. Ferring, European Patent No. 112,809A, discloses compounds with a Mpr unit at 1, a Cys at 6 and a VSP-antagonist tail which are described as oxytocin antagonists.
U.S. Pat. No. 4,508,645 describes structures which have a 6-Pen unit along with an amino containing unit at 1 such as Cys or Pen as well as an oxytocin-like tail. Such compounds have V.sub.1 -vasopressin antagonist activity.
U.S. Pat. No. 4,491,577 is representative of many prior art disclosures of vasopressin antagonists which have a 6-Cys unit structure.
I have now found that vasopressin-like compounds can be prepared whose structures have the bulky penicillamine unit at the tertiary 6-position. The resulting compounds have unexpected binding activity at vasopressin receptor sites.
In the description herein and in the claims, the nomenclature common in the art of peptide and, more specifically, vasopressin chemistry is used. When no confirguration is noted, the amino acid unit is in the L, or naturally occuring, form. The thio members of the .beta.-mercaptopropionic acid (position 1) and penicillamine (position 6) units are added for clarity in certain structural formulas.
When the term, "vasopressin" or "VSP", is used, it means arginine vasopressin (AVP) unless otherwise modified.
"Alk" in formula I below and thereafter represents a lower alkyl of 1-4 carbons as a substituent which may be attached to the oxygen substituent of a tyrosine unit. Such alkyl substituents include methyl, ethyl, n-propyl, isopropyl or butyl. Preferably, Alk is methyl or ethyl.
Exemplary of the peptide art designations used herein are the following: Mpr, .beta.-mercaptopropionic acid; OXT, oxytocin; Pro, proline; Pen, penicillamine; Gly, glycine; Tyr, tyrosine; Tyr(Alk), O-alkyltyrosine; Phe, phenylalanine; Phe(Alk), 4-alkylphenylalanine; Val, valine; Ile, isoleucine; Lys, lysine, Arg, arginine; Asn, asparagine; Tos, tosylate; BHA, benzhydrylamine; DIEA, diisopropylethylamine; 4-MeBzl, 4-methylbenzyl; TFA, trifluoroacetic acid; DCC, dicyclohexylcarbodiimide; HOBT, 1-hydroxybenzotriazole; ACM, acetamidomethyl.